Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial
Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial
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DOI：
10.1016/s0140-6736(14)60162-8
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发表时间：
2014-08-23
期刊：
影响因子：
168.9
通讯作者：
Maartens, Gary
中科院分区：
文献类型：
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作者：
Rangaka, Molebogeng X.;Wilkinson, Robert J.;Maartens, Gary
背景 抗逆转录病毒治疗可降低患结核病的风险，但结核病在艾滋病毒感染者中比未感染艾滋病毒的人中更常见。我们的目的是评估异烟肼预防性治疗对同时接受抗逆转录病毒治疗的 HIV-1 感染者患结核病风险的影响。 方法 在南非 Khayelitsha 进行的这项实用随机双盲、安慰剂对照试验中，我们随机分配 (1:1) 患者接受异烟肼预防性治疗或安慰剂，为期 12 个月（可在 15 个月内完成）。随机化是通过随机数生成软件完成的。参与者、医生和药房工作人员不知道分组情况。主要终点是发生结核病的时间（确定的、可能的或可能的）。我们通过痰培养筛查排除了结核病。我们进行了修改后的意向治疗分析，并排除了所有随机分配到在接受研究药物之前退出的组或其基线痰培养结果表明患有流行性结核病的患者。这项研究已在 ClinicalTrials.gov 注册，编号为 NCT00463086。结果 2008 年 1 月 31 日至 2011 年 9 月 31 日期间，1329 名参与者被随机分配接受异烟肼预防性治疗 (n=662) 或安慰剂 (n=667)，并为分析提供了 3227 人年的随访。我们记录了 95 起结核病病例；异烟肼预防性治疗组有 37 例（每 100 人年 2.3 例，95% CI 1.6-3.1），安慰剂组有 58 例（每 100 人年 3 6 例，2.8-4.7；风险比 [HR] 0.63，95% CI 0.41-0.94）。由于异烟肼预防性治疗组 662 名受试者中的 19 名受试者和安慰剂组 667 名受试者中的 10 名受试者出现 3 级或 4 级丙氨酸转氨酶浓度升高（风险比 1.9，95% CI 0.90-4.09），因此停止研究药物。我们注意到没有证据表明异烟肼预防性治疗的效果仅限于结核菌素皮试或干扰素γ释放试验呈阳性的患者（阴性测试患者的调整后HR为0.43 [0.21-0.86]和0.43 [0.20-0.96]；阳性测试为0.86 [0.37-2.00]和0.55 [0.26-1.24]，如果没有更具预测性的测试或多变量算法来预测益处，则应向中度或高发地区所有接受抗逆转录病毒治疗的患者推荐异烟肼预防性治疗，无论结核菌素皮试或干扰素γ释放测定状态如何。
Background Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.Methods For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086.Findings 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2.3 per 100 person-years, 95% CI 1.6-3.1), and 58 in the placebo group (3 6 per 100 person-years, 2.8-4.7; hazard ratio [HR] 0.63, 95% CI 0.41-0.94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1.9, 95% CI 0.90-4.09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0.43 [0.21-0.86] and 0.43 [0.20-0.96]; for positive tests 0.86 [0.37-2.00] and 0.55 [0.26-1.24], respectively).Interpretation Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status.